The innate immune system of animals and plants has evolved to maintain a healthy load of endemic microorganisms. Beneficial commensals proliferate in various compartments of multicellular organisms; this is tolerated by the innate immune system. On the other hand, the innate immune system actively attempts (and, mostly succeeds) to suppress growth of harmful pathogens. Multiple signals from both host and microbe are integrated to produce an appropriate level of immunogenic response. Large gaps in our knowledge of the molecular and cellular coordination of pathogen response remain. The nematode Caenorhabditis elegans is a simple, genetically-tractable model host for the study of innate immunity. Recent work has demonstrated that the C. elegans protein CED-1, a homologue of mammalian scavenger receptors, regulates activation of the non-canonical unfolded protein response (UPR) during the host innate immune response. Moreover, it has been demonstrated that the nervous system, via the G-protein coupled receptor (GPCR) OCTR-1, controls CED-1-mediated immune responses. For this proposal, there are three specific Aims: 1) determine the spatial requirement for CED-1 activity during an innate immune response, 2) analysis of neural circuits that regulate innate immunity, and 3) characterization of pathways that regulate CED-1-dependent abu gene expression. This study will identify innate immune pathways upstream and downstream of OCTR-1/CED-1. This work will help in characterizing molecular pathways, cell autonomous and non-cell autonomous, that contribute to immunity to human pathogens and tolerance of microbial gut communities.